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Bioinformatics analysis identified TCP1 and NOTCH1 as potential target molecules to overcome 5-fluorouracil
Sonexai Kidoikhammouan1, Nopkamol Kanchanangkul2, Worachart Lert-Itthiporn2
1Biomedical Sciences Program, Graduate School, Khon Kaen University, Thailand.
Background:
Late diagnosis and chemotherapy resistance, particularly to 5-fluorouracil (5-FU), contribute to the low survival rate in cholangiocarcinoma (CCA) patients. Identifying relevant genes and pathways, as well as novel targeted molecules, is crucial to overcoming 5-FU resistance and improving treatment outcomes for CCA patients.
Objectives:
This study aimed to determine the potential molecules associated with 5-FU resistance in CCA cells.
Material And Methods:
Transcriptomic datasets from 4 stable 5-FU-resistant cell lines and their corresponding parental lines were retrieved from the Gene Expression Omnibus. A series of bioinformatics analyses were conducted to identify key genes upregulated in 5-FU-resistant cells compared to their parental counterparts. The expression levels of candidate genes identified through bioinformatics analysis were validated in CCA tissues and cell lines.
Results:
Differential gene expression, protein-protein interaction, and Hub genes analysis revealed 8 genes that were significantly upregulated in 5-FU resistance cells compared to their parental cells. Six of the 8 genes, including TCP1, RPS6, RPS29, HSPA5, RPS15A, and NOTCH1, were upregulated in patient CCA tissues. Using real-time PCR, only the expression levels of NOTCH1 and TCP1 were significantly higher in the 5-FU insensitive CCA cell lines, KKU-213A and KKU-213B, than that of the 5-FU sensitive CCA cell line, KKU-055. A similar result was observed in stable 5-FU-resistant cell lines (KKU-213A-FR and KKU-213B-FR) compared to their parental cells.
Conclusions:
The bioinformatic analysis and PCR results revealed that NOTCH1 and TCP1 might be associated with 5-FU resistance and serve as potential molecular targets to enhance 5-FU sensitivity in CCA cells.
Insights
This study identified NOTCH1 and TCP1 as key genes linked to 5-fluorouracil (5-FU) resistance in cholangiocarcinoma (CCA). These findings suggest NOTCH1 and TCP1 as potential targets to improve 5-FU chemotherapy effectiveness in CCA patients.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Cholangiocarcinoma (CCA) survival rates are low, partly due to late diagnosis and resistance to chemotherapy, especially 5-fluorouracil (5-FU).
- Identifying molecular mechanisms driving 5-FU resistance is critical for developing effective CCA treatments.
Purpose of the Study:
- To identify potential molecular targets associated with 5-FU resistance in CCA cells.
- To explore novel therapeutic strategies for overcoming 5-FU resistance in cholangiocarcinoma.
Main Methods:
- Transcriptomic data from 5-FU-resistant and parental CCA cell lines were analyzed using bioinformatics.
- Differential gene expression, protein-protein interaction, and hub gene analyses were performed.
- Candidate gene expression was validated in CCA tissues and cell lines via real-time PCR.
Main Results:
- Eight genes were significantly upregulated in 5-FU-resistant CCA cells compared to parental cells.
- NOTCH1 and TCP1 showed significantly higher expression in 5-FU-insensitive CCA cell lines and resistant cell lines.
- Six identified genes, including NOTCH1 and TCP1, were also upregulated in patient CCA tissues.
Conclusions:
- NOTCH1 and TCP1 are potentially associated with 5-FU resistance in cholangiocarcinoma.
- These genes represent promising molecular targets for enhancing 5-FU sensitivity in CCA treatment.
- Further research into NOTCH1 and TCP1 could lead to improved therapeutic outcomes for CCA patients.
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